Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1
Aaron M. Fond, … , Robert S. Kiss, Kodi S. Ravichandran
Aaron M. Fond, … , Robert S. Kiss, Kodi S. Ravichandran
Published July 1, 2015; First published June 15, 2015
Citation Information: J Clin Invest. 2015;125(7):2748-2758. https://doi.org/10.1172/JCI80300.
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Research Article Cardiology

Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1

Abstract

Macrophages clear millions of apoptotic cells daily and, during this process, take up large quantities of cholesterol. The membrane transporter ABCA1 is a key player in cholesterol efflux from macrophages and has been shown via human genetic studies to provide protection against cardiovascular disease. How the apoptotic cell clearance process is linked to macrophage ABCA1 expression is not known. Here, we identified a plasma membrane–initiated signaling pathway that drives a rapid upregulation of ABCA1 mRNA and protein. This pathway involves the phagocytic receptor brain-specific angiogenesis inhibitor 1 (BAI1), which recognizes phosphatidylserine on apoptotic cells, and the intracellular signaling intermediates engulfment cell motility 1 (ELMO1) and Rac1, as ABCA1 induction was attenuated in primary macrophages from mice lacking these molecules. Moreover, this apoptotic cell–initiated pathway functioned independently of the liver X receptor (LXR) sterol–sensing machinery that is known to regulate ABCA1 expression and cholesterol efflux. When placed on a high-fat diet, mice lacking BAI1 had increased numbers of apoptotic cells in their aortic roots, which correlated with altered lipid profiles. In contrast, macrophages from engineered mice with transgenic BAI1 overexpression showed greater ABCA1 induction in response to apoptotic cells compared with those from control animals. Collectively, these data identify a membrane-initiated pathway that is triggered by apoptotic cells to enhance ABCA1 within engulfing phagocytes and with functional consequences in vivo.

Authors

Aaron M. Fond, Chang Sup Lee, Ira G. Schulman, Robert S. Kiss, Kodi S. Ravichandran

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Figure 1

Primary resident peritoneal macrophages rapidly upregulate ABCA1 in response to apoptotic cell recognition.

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Primary resident peritoneal macrophages rapidly upregulate ABCA1 in resp...
(A) Apoptotic Jurkat cells or control medium was injected intraperitoneally into C57BL/6 mice (n = 8/group). Abca1 mRNA in peritoneal cells was measured after 4 hours (mean ± SEM). Representative of 2 experiments. *P < 0.05 (t test). Apop, apoptotic. (B) Apoptotic murine thymocytes (tinted) or control medium (open) was injected intraperitoneally into C57BL/6 mice. After 6 hours, peritoneal lavage cells were analyzed by flow cytometry for IgM, CD11b, and ABCA1. Representative histograms of ABCA1 staining of B cells (IgM+) and macrophages (IgM–, CD11b+) are shown with quantification from 2 independent experiments on the right (mean ± SEM). *P < 0.05 (t test). (C) Cultured WT peritoneal macrophages incubated with apoptotic human Jurkat cells were analyzed for mRNA levels of murine Abca1, Abcg1, and Cd36 over a time course. Representative of 2 independent experiments. (D) Surface expression of ABCA1 on primary peritoneal macrophages by flow cytometry before (gray trace) and 6 hours after (green) treatment with apoptotic thymocytes or the LXR agonist 1317 (positive control [see Figure 2A], purple). ABCA1 staining on thymocytes (red) and control antibody staining on peritoneal macrophages (black) are also shown. Representative of 3 independent experiments. (E) Representative immunoblot of ABCA1 expression in primary peritoneal macrophages after 6-hour incubation with apoptotic Jurkat cells (left) and densitometry quantification from 4 independent experiments (right, mean ± SEM). *P < 0.05 (paired t test). (F) Cholesterol efflux to the acceptor ApoA1 by primary peritoneal macrophages after apoptotic cell treatment was measured over 4 hours (mean ± SD).